The overall long-term objective of this proposal is to develop a patient-oriented research program in opioid pharmacology, specifically directed towards the therapy of cancer pain and of substance abuse. A principal component of this program will be the development of beginning clinical investigators. The specific research objectives are to 1) expand existing research which investigates mechanisms of variability in human opioid disposition, pharmacodynamics and clinical efficacy, and endeavors to optimize opioid therapy of cancer pain and of substance abuse, 2) facilitate program expansion into underutilized therapies such as nonsteroidal antiinflammatory drugs and emerging issues such as outpatient postoperative pain therapy, and 3) mentor beginning clinician-scientists in patient-oriented research, utilizing the above framework to spawn independent research programs. A critical focus will be interfacing in vitro and in vivo aspects of human drug disposition and efficacy, and translating recent explosive discoveries in basic enzymology and pharmacogenetics of drug disposition into clinical strategies for optimized therapy. Oral and parenteral opioids ar the primary therapy for opiate addiction and cancer pain. Methadone maintenance is the cornerstone of opiate abuse therapy, a vital and effective strategy for HIV/AIDS risk reduction, and is widely used for cancer pain treatment. l-alpha-acetylmethadol (LAAM) is the first new opioid in three decades approved for opiate abuse. Oral transmucosal fentanyl (OTFC) is the first drug ever specifically developed for treating breakthrough cancer pain. All these opioids are characterized by extreme, unexplained, and unpredictable interindividual variability in their pharmacokinetics, causing inadequate pain treatment, opioid abstinence syndrome, treatment failures, and frequent unwanted side effects. Unexplained age- and gender-dependent variabilities also prevail. These opioids are metabolized by cytochrome P450 in the intestine and liver. The mechanisms of individual and age-dependent variability in the metabolism of these opioids are, however, unknown. Indeed, little is known about the P450s responsible for human clinical metabolism of OTFC, LAAM and methadone (and its individual enantiomers, which have divergent efficacies), and the factors affecting these P450s. Consequences for clinical drug effect are similarly unknown. Experiments in vitro will use human liver and intestinal microsomes to identify relevant P450 isoforms and probe enantiomeric and drug-drug interactions, while complementary in vivo clinical investigations will verify these identifications and establish the influence of age, gender, and diet on opioid disposition and pharmacologic effects. Successful identification of the P450s and factors affecting metabolism, clearance, blood concentrations, and clinical effects of OTFC, LAAM and methadone will improve the clinical outcome and reduce the costs of opiate addiction and cancer pain treatment, and provide insights into age-, gender-, and environmentally-dependent changes in drug disposition.